Key result
NCX1 transduction normalizes profibrotic TGFβ responses in Friedreich's ataxia fibroblasts by restoring calcium regulation.
Why the study?
Cardiac fibrosis contributes to cardiomyopathy in Friedreich’s ataxia, but the underlying mechanisms of fibrotic responses remain unknown.
In Friedreich's ataxia fibroblasts, NCX1 downregulation causes cytosolic calcium dysregulation that amplifies TGFβ-induced fibrotic reprogramming, identifying a potential therapeutic target for FA cardiomyopathy.
NCX1 may be a fibrosis target in Friedreich ataxia; leaves open translation to cardiomyopathy therapy pending in vivo validation.
Friedreich’s ataxia (FA) is an inherited disease caused by loss of frataxin ( FXN ) and characterized by neurodegeneration and fatal cardiomyopathy. Cardiac fibrosis contributes to cardiomyopathy by stiffening the heart wall, yet the underlying mechanisms remain unknown. Here, we investigated pro-fibrotic predisposition in FA patient-derived fibroblasts, focusing on the role of cytosolic calcium (Ca) in TGFβ-driven fibroblast-to-myofibroblast transition (FMT). We found pro-fibrotic transcriptional priming in FA fibroblasts, alongside elevated expression of genes controlled by the Ca-responsive transcription factor NFAT. Upon FMT, FA myofibroblasts showed amplified induction of pro-fibrotic ( CCN2 , NOX4 ) and suppression of anti-fibrotic ( CCN3 ) genes, which were inversely correlated with residual FXN . Mechanistically, FA fibroblasts exhibited elevated cytosolic Ca and strongly downregulated expression of the Na-Ca exchanger NCX1, which directly correlated with FXN . Furthermore, NCX1 inhibition in control fibroblasts recapitulated FA Ca phenotypes, whereas NCX1 transduction in FA fibroblasts normalized Ca dynamics and blunted CCN2 induction in FMT. These findings highlight NCX1 as a modulator of fibrotic reprogramming in FA and identify Ca dyshomeostasis as an intrinsic mechanism of fibrosis that could be targeted therapeutically.
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Степанова et al. (2026) studied Friedreich's ataxia (n=24). Friedreich's ataxia genotype (FXN deficiency) vs. Healthy control genotype was evaluated on Fibroblast-to-myofibroblast transition and fibrotic gene expression profiles. Friedreich's ataxia fibroblasts showed amplified profibrotic responses to TGFβ due to cytosolic calcium dysregulation caused by NCX1 downregulation, which was normalized by NCX1 transduction.
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